Efforts aimed at understanding the signal transduction mechanisms utilized during T cell activation provide a foundation for developing strategies to pharmacologically or genetically manipulate T cells. The actin cytoskeleton plays a key role in T cell activation and function and is thought to organize lymphocyte signaling complexes at the immunological synapse (IS). A major focus of research in this area has been the Wiskott- Aldrich Syndrome protein (WASp), which plays a clear role in T cell activation. However, recent data suggest that WASp may not be required for the formation of F-actin at the IS, so other mechanisms must contribute to this phenomenon. This application focuses on the leukocyte-specific homologue of Cortactin, HS1, a multi-domain signaling molecule that binds actin and the Arp2/3 Complex. Although HS1 regulates F-actin polymerization in vitro, no functional role for HS1 in controlling actin reorganization in lymphocytes has been established. Our preliminary data demonstrate that HS1 is required for the accumulation of F-actin at the IS during T cell activation. Therefore, we hypothesize that HS1 cooperates with the known actin- regulatory proteins, including Vav1 and Itk, to reorganize the actin cytoskeleton during T cell activation. [unreadable] [unreadable] [unreadable]